ABSTRACT Cell therapy holds promise for CNS disorders. This is suggested by clinical benefits in some Parkinson's disease (PD) patients who received transplantation of human fetal mesencephalic tissues to replace degenerated midbrain dopamine (mDA) neurons. The ability to produce functional neurons efficiently from human pluripotent stem cells (PSCs) expands the prospect of cell therapy. However, cell therapy for many neurological conditions faces major hurdles. In particular, transplanted neurons often fail to reconstruct a functional circuit that is specific to lost function. In PD, DA neurons are often transplanted directly into the striatum, rather than their home location substantial nigra. Consequently, the grafted cells and their repaired circuit lose appropriate inputs for functional modulation. To address these critical issues, we will reconstruct the nigra-striatal circuit by cell transplantation to the nigra in a PD model mouse and determine if the grafted human mDA neurons project specifically to the striatum to form functional circuit and if the reconnection is sped up by regulating graft activity (Aim 1). Furthermore, we will explore to regulate the neural circuit repaired by transplanted cells by expressing active or inhibitory form of DREADD (designer receptor exclusively activated by designer drug) in hPSCs so that the therapeutic outcomes may be refined (Aim 2). Information gained from this study will be instrumental for restoring and regulating neural circuitry in PD and other neurological conditions.